Abstract

Among the cytokines that regulate B-cell homeostasis are the TNF-like ligands B-lymphocyte
stimulator (BLyS; also B-cell activation factor) and a proliferation-inducing ligand
(APRIL). BLyS and APRIL share two receptors; that is, B-cell maturation antigen and
transmembrane activator and CAML interactor. Therapeutic approaches using biologics
are limited for treatment of lupus patients. One previously approved drug is belimumab,
which antagonizes the B-cell stimulator BLyS. Atacicept, another biologic inhibiting
BLyS and APRIL, was terminated for serious adverse events - raising the question of
whether APRIL should be neutralized in autoimmune diseases.

Editorial

Treamtrakanpon and coworkers analyzed B-lymphocyte stimulator (BLyS; also B-cell activation
factor) and a proliferation-inducing ligand (APRIL) expression in patients with lupus
nephritis and observed a correlation with renal disease activity and APRIL serum levels
[1]. In addition, the authors describe that, upon treatment with immunosuppressors, nonresponding
patients had higher APRIL serum levels. They thus concluded that APRIL could be a
potential biomarker for predicting difficult-to-treat cases of lupus nephritis, and
propose the use of APRIL antagonists such as atacicept for treatment of lupus nephritis
patients with high APRIL serum levels.

These conclusions might be premature, as Treamtrakanpon and coworkers have not found
a correlation between the level of APRIL in kidney tissue and renal disease activity.
Another hypothesis could be that APRIL has a protective effect in autoimmune diseases.
Indeed, the crucial role of BLyS in B-cell maintenance became evident by the analysis
of BLyS-deficient mice displaying lower numbers of mature B cells and of BLyS transgenic
mice developing severe B-cell hyperplasia. Although APRIL can trigger different B-cell
responses in vitro, including proliferation and survival of human and murine B cells, it is less critical
than BLyS in B-cell maintenance as APRIL knockout and transgenic mice reveal no gross
abnormalities in lymphoid homeostasis [2]. In fact, APRIL was found to modulate specific B-cell responses such as IgA isotype
switching, increased IgM secretion and B1 cell activity.

Meanwhile, BLyS is an established promoter of B-cell-triggered autoimmmune diseases
such as systemic lupus erythematosus and rheumatoid arthritis, whereas the role of
APRIL in these pathologies is rather controversial. Neutralizing BLyS with the mAb
belimumab displayed a modest, although statistically significant, therapeutic effect
in systemic lupus erythematosus [3,4]. But blocking both BLyS and APRIL with atacicept (TACI-Fc) was associated with a
pronounced reduction of immunoglobulins, and occurrence of serious infections led
to a premature termination of a phase II/III trial in lupus nephritis [5]. The combination of mycofenolate mofetil with atacicept may have contributed to the
decrease of immunoglobulins. However, at acicept combined with another drug such as
methotrexate in patients with rheumatoid arthritis was also associated with a significant
reduction of immunoglobulins (especially IgM). In this autoimmune disease, atacicept
failed to demonstrate efficacy on American College of Rheumatology 20 criteria [6]. In contrast, administration of belimumab showed a modest but significant efficacy
using the same evaluation criteria in rheumatoid arthritis [7].

These findings suggest distinct roles for BLyS and APRIL in lupus and other B-cell-mediated
autoimmune diseases. Elevated serum levels are found for both cytokines in lupus patients,
and for BLyS there is a consensus in the literature that this reï¬‚ects its disease-promoting
activity. Elevated APRIL serum levels, however, have been - depending on the respective
study - either positively or negatively correlated with disease features [8]. One possible explanation for this discrepancy could be differences in the patient
cohorts analyzed. A recent study by Jacob and colleagues analyzed a murine lupus model
in APRIL-deficient mice and observed elevated numbers of splenocytes, increased autoantibody
production and a tendency towards increased IgG production [9]. Notably, ectopic APRIL expression does not result - in contrast to BLyS transgenic
mice - in lupus-like symptoms. In fact, we found that APRIL does dampen collagen-induced
arthritis, the most common mouse model for human arthritis [10].

Experimental mouse models for autoimmune diseases obviously cannot entirely mimic
human diseases. Nevertheless, in vivo data are accumulating that do not support a disease-supporting role for APRIL in B-cell-mediated
autoimmunity. The study by Treamtrakanpon and colleagues is putting forward the need
to better elucidate the role of APRIL in B-cell-driven diseases before concluding
a therapeutic approach.